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Introduction: Neuromonitoring represents a cornerstone in the comprehensive management of patients with traumatic brain injury (TBI), allowing for early detection of complications such as increased intracranial pressure (ICP) [1]. This has led to a search for noninvasive modalities that are reliable and deployable at bedside. Among these, ultrasonographic optic nerve sheath diameter (ONSD) measurement is a strong contender, estimating ICP by quantifying the distension of the optic nerve at higher ICP values. Thus, this scoping review seeks to describe the existing evidence for the use of ONSD in estimating ICP in adult TBI patients as compared to gold-standard invasive methods. Materials and Methods: This review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews, with a main search of PubMed and EMBASE. The search was limited to studies of adult patients with TBI published in any language between 2012 and 2022. Sixteen studies were included for analysis, with all studies conducted in high-income countries. Results: All of the studies reviewed measured ONSD using the same probe frequency. In most studies, the marker position for ONSD measurement was initially 3 mm behind the globe, retina, or papilla. A few studies utilized additional parameters such as the ONSD/ETD (eyeball transverse diameter) ratio or ODE (optic disc elevation), which also exhibit high sensitivity and reliability. Conclusion: Overall, ONSD exhibits great test accuracy and has a strong, almost linear correlation with invasive methods. Thus, ONSD should be considered one of the most effective noninvasive techniques for ICP estimation in TBI patients. [ABSTRACT FROM AUTHOR]

Introduction Optic nerve sheath diameter (ONSD) measured using ultrasonography has been widely used as a surrogate marker of elevated intracranial pressure. However, literature is sparse on the correlation between ONSD and ventriculoperitoneal (VP) shunt function, especially in adults with hydrocephalus. Our study was designed to assess the correlation between ONSD measured using ultrasonography before and 12 hours after VP shunt placement and the success of VP shunt placement assessed using computed tomography (CT) of the brain. Materials and Methods Fifty-one patients between 16 and 60 years of age, with obstructive hydrocephalus scheduled for VP shunt surgery were included in this prospective, observational study. ONSD measurements were obtained from both eyes prior to induction of anesthesia, immediately after the surgery, and at 6, 12, and 24 hours after the surgery. An average of three readings was obtained from each eye. Cerebrospinal fluid (CSF) opening pressure was noted after entry into the lateral ventricle. Noncontrast CT (NCCT) brain was obtained 12 hours after the surgery and was interpreted by the same neurosurgeon for signs of successful VP shunt placement. Results There was a significant reduction in ONSD in the postoperative period compared to ONSD measured preoperatively. The average ONSD (mean ± standard deviation) measured prior to induction of anesthesia, immediately after the surgery, and at 6, 12, and 24 hours after the surgery was 5.71 ± 0.95, 5.20 ± 0.84, 5.06 ± 0.79, 4.90 ± 0.79, and 4.76 ± 0.75 mm, respectively. The mean CSF opening pressure was 19.6 ± 6.9 mm Hg. Postoperative NCCT brain revealed misplacement of the shunt tip in only one patient. Conclusion ONSD measured using ultrasonography may be used as a reliable indicator of VP shunt function in adults with obstructive hydrocephalus. [ABSTRACT FROM AUTHOR]

The effects of brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and visual function were assessed in rat and mouse models of optic nerve (ON) crush. ONs were crushed on Day 1, followed by intravitreal injections of a vehicle or BDNF on Days 1 and 8. The spatial frequency threshold was measured using optokinetic tracking on Days 7 and 14. On Day 15, ganglion cell complex (GCC) thickness was quantified using optical coherence tomography. Furthermore, all eyes were enucleated for immunohistochemical analysis of the surviving RGC somas and axons. BDNF significantly reduced the RGC soma in mice and increased GCC thickness in intact eyes, with apparent axonal swelling in both species. It displayed significantly greater RGC soma survival in eyes with ON injury, with moderately thicker axonal bundles in both species and a thicker GCC in rats. Visual function was significantly reduced in all ON-crushed animals, regardless of BDNF treatment. Thus, we obtained a comprehensive analysis of the structural and functional impact of BDNF in intact and ON-crushed eyes in two rodent models. Our results provide a foundation for further BDNF evaluation and the design of preclinical studies on neuroprotectants using BDNF as a reference positive control. [ABSTRACT FROM AUTHOR]

The development of the optic nerve and its surrounding tissues during the early fetal period is a convoluted period because it spans both the organogenesis period and the fetal period. This study details the microscopic anatomy and histoembryology of the optic nerve in embryos during the early fetal period, including the second half of the first trimester of pregnancy. Serial sections through the orbit of variously aged embryos allowed us to analyze the nerve in both longitudinal and transverse aspects. A histological assessment and description of the structures surrounding and inside the nerve were performed, highlighting the cellular subtypes involved. By employing immunohistochemical techniques, we could characterize the presence and distribution of astrocytes within the optic nerve. Our findings suggest that by the 8th gestational week (WG) the structures are homologs to all the adult ones but with an early appearance so that maturation processes take place afterward. By this age, the axons forming the nerve are definitive adult axons. The glial cells do not yet exhibit adult phenotype, but their aspect becomes adult toward the 13th week. During its development the optic nerve increases in size then, at 14 weeks, it shrinks considerably, possibly through its neural maturation process. The morphological primordium of the blood–nerve barrier can be first noted at 10 WG and at 13 WG the morphological blood–nerve barrier is definitive. The meningeal primordium can be first noted as a layer of agglomerated fibroblasts, later toward 13 WG splitting in pachymeninx and leptomeninges and leaving space for intrinsic blood vessels. [ABSTRACT FROM AUTHOR]

This article examines the research trends in optic nerve sheath diameter (ONSD) monitoring through a bibliometric study. The study reveals a consistent increase in the number of articles on ONSD, with the highest number of publications in 2023. The analysis of keywords indicates that ONSD monitoring is widely used for predicting neurological outcomes and has gained significance in non-neurological intensive care settings. The article also highlights the potential of ONSD monitoring for non-invasive intracranial pressure measurement in neurosurgery. However, the study's inclusion of all PubMed titles may have led to the repetition of keywords, limiting its findings. Nonetheless, the article offers valuable insights into the current state of research in ONSD monitoring. [Extracted from the article]

A 15-year-old female presented with headaches and bilateral vision loss. Fundoscopic examination revealed bilateral optic nerve oedema as well as peripheral retinal haemorrhages. Magnetic resonance imaging of the brain showed findings consistent with bilateral optic neuritis. The patient was started on high dose intravenous corticosteroids but her vision failed to improve. The presence of retinal haemorrhages raised concern that a vasculitis was underlying her symptoms, prompting an extensive work-up, which was unrevealing. Plasmapheresis was initiated and the patient's vision eventually improved to 20/20 in both eyes. Ultimately, she was found to be positive for myelin oligodendrocyte glycoprotein (MOG) antibodies, consistent with a diagnosis of MOG-associated optic neuritis. The patient's course was typical for MOG-associated optic neuritis but her peripheral retinal haemorrhages were atypical, which created diagnostic uncertainty. It is important to be aware of the possibility of retinal findings in this disease. We also review potential causes for retinal haemorrhages in optic neuritis. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the role of optic nerve diffusion status on cranio-orbital magnetic resonance imaging (MRI) in predicting visual prognosis in cases of methanol intoxication. Diffusion-weighted imaging (DWI) from 16 eyes of eight patients who were admitted to our clinic due to methanol intoxication was analysed retrospectively. The relationship between clinical and laboratory findings, treatment regimen, visual prognosis, and imaging findings was investigated. Diffusion restriction (DR) of the optic nerve on DWI was observed in seven (43%) eyes. Regardless of the clinical and laboratory characteristics and treatment regimen, visual acuity (VA) improved in eyes in which restricted diffusion regressed over the follow-up period. DWI of the optic nerve during the acute phase of methanol poisoning may provide prognostically important data. Improvement of DR during follow-up may be an indicator of an increase in VA. [ABSTRACT FROM AUTHOR]

To determine whether more severe baseline damage impedes measurement of minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (RNFLT) change in glaucoma patients because of a floor effect. Prospective, longitudinal cohort study in a hospital-based setting. The study included patients with open-angle glaucoma and healthy control subjects. Participants had at least 5 years of follow-up with OCT every 6 months. Baseline global and sectorial MRW and RNFLT values were classified as within normal limits, borderline, or outside normal limits based on reference normative values. Regression analysis was used to determine the magnitude and significance of MRW and RNFLT change. Additionally, the follow-up period for each participant was divided into 2 equal halves (first and second periods) to determine whether there was attenuation of MRW and RNFLT change with follow-up time. Rates of global and sectoral MRW and RNFLT changes (slopes). A total of 97 patients with glaucoma (median age, 70.3 years) and 42 healthy subjects (median age, 64.8 years) were followed for a median of 6.9 years and 7.0 years, respectively. The median mean deviation of the visual field in glaucoma patients was –4.30 decibels (dB) (interquartile range, –7.81 to –2.06 dB; range, –20.68 to 1.37 dB). Statistically significant changes in global and sectoral MRW and RNFLT were detected across all baseline classifications; however, there was a tendency for less change with increasing baseline damage. In glaucoma patients, RNFLT slopes, but not MRW slopes, were significantly more positive (less change) in the second period compared with the first. There were also no differences in MRW or RNFLT slopes in the first and second periods in healthy subjects. Significant MRW and RNFLT changes were detected at all levels of baseline damage. However, an attenuation in the rate of RNFLT change compared with MRW indicates an earlier floor effect in RNFLT measurements globally and in equivalent sectors. Because the axonal component of these measurements should be equivalent, our results suggest important differences in tissue remodeling at the level of the optic nerve head and peripapillary retina. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport across the glial lamina. Fluid homeostasis and waste removal are vital for retinal function, making the ocular glymphatic fluid pathway a potential route for targeted manipulation to combat blinding ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Several lines of work investigating the bidirectional ocular glymphatic transport with varying methodologies have developed diverging mechanistic models, which has created some confusion about how ocular glymphatic transport should be defined. In this review, we provide a comprehensive summary of the current understanding of the ocular glymphatic system, aiming to address misconceptions and foster a cohesive understanding of the topic. [ABSTRACT FROM AUTHOR]

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death. [ABSTRACT FROM AUTHOR]

Introduction: Primary Open-Angle Glaucoma (POAG) is considered a leading cause of blindness among all others. Different technologies such as Scanning Laser Polarimetry (SLP) and Optical Coherence Tomography (OCT) closely correlate in measuring structural parameters of the Retinal Nerve Fiber Layer (RNFL) and Optic Nerve Head (ONH). Visual impairment related to glaucomatous damage is attributed to the RNFL. Earlier studies have shown that retro-bulbar optic nerve thickness is reduced in glaucoma and have suggested that this is also the result of RNFL destruction. Aim: To investigate the correlation between the orbital and intraocular portions of the optic nerve among POAG patients. Materials and Methods: This was a hospital-based crosssectional study done in a tertiary care ophthalmic institute from October 2019 to February 2021. One eye of 32 volunteers with newly diagnosed POAG underwent optic disc analysis using OCT and echographic measurements of the retrobulbar optic nerve. For statistical calculations, Statistical Package for Social Sciences (SPSS) Statistics version 20.0 software (IBM Corp., Armonk, NY, USA) was used. Spearman's rho (rs) was used as the index of correlation between retrobulbar optic nerve dimensions and ONH topographical data. A correlation between OCT-based RNFL and optic disc parameters was compared with retrobulbar optic nerve dimensions measured with the help of Ultrasonography-Brightness (USG B) Scan. Results: Orbital Optic Nerve Diameter (OND) and Optic Nerve Cross-sectional Area (ONCSA) significantly and positively correlated with Neuro-retinal Rim (NR) area (OND: p-value=0.00001; ONCSA: p-value=0.00001) and average nerve fiber layer thickness (OND: p-value=0.0001; ONCSA: p-value=0.00002). The Retrobulbar ONCSA-to-disc area ratio (ONCSA/D) was found to have a statistically demonstrable positive correlation with Neuro-retinal Rim Area/Disc area ratio (NR/D) (p=0.00003). Conclusion: This study showed that retrobulbar optic nerve dimensions correlate well with SD-OCT-based ONH parameters. Echographic measurements of the retrobulbar optic nerve add a new biomarker in the diagnosis of glaucoma. [ABSTRACT FROM AUTHOR]

Introduction: Myopia is a prevalent refractive condition associated with higher occupational groups and education. Contributing data from a region like Saudi Arabia adds to the global understanding of myopia progression, potentially uncovering patterns or risk factors that may differ from those observed in other parts of the world. Aim: To estimate myopia progression among junior medical students. Materials and Methods: This was a one-year longitudinal cohort study conducted on 85 students at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Demographics, detailed ocular history, use of electronic devices, and other related risk factors were collected at the start of the study. Students underwent a comprehensive eye examination including visual acuity, autorefraction, ocular biometry, and Spectral Domain-Optical Coherence Tomography (SD-OCT) of the macula and optic nerve at the start and end of the study. Progression of myopia over one year and its associations were assessed using pairedsamples t-test for a single group, while =two-group comparison was tested with Independent t-tests and one-way Analysis of Variance (ANOVA), respectively. Results: This cohort study involved 85 medical students (41 men and 44 women) aged between 19 and 23 years. Myopia prevalence was 76.5% (65/85) on the first visit. One participant progressed from hyperopia to myopia, five from initial emmetropia to myopia, four from mild to moderate myopia, and one from moderate to high myopia. A significant myopic shift was observed in the second visit in both eyes {Right Eye (RE): -0.3D, p-value=0.001; Left Eye (LE): -0.2 D, p-value=0.015}. The myopic shift in male participants from a mean±SD of -1.1±1.6 D (RE) and -1.0±1.5 D (LE) to -1.5±1.7 D (RE) and -1.4±1.7 D (LE) in the one year follow-up was statistically significant (RE: p-value=0.006; LE: p-value=0.004). Myopia prevalence was significantly related to the hours spent reading for learning/studying and hours spent watching TV at the first visit (p-value=0.023, p-value=0.046, respectively) and total weekly average screen time at the second visit (p-value=0.002). Conclusion: The medical students had a significant myopic shift over one year, which was associated with longer hours spent reading. The factors associated with the rapid refraction change should be identified to reduce myopic shift among medical students. [ABSTRACT FROM AUTHOR]

Purpose: Despite mounting evidence indicating that aquaporin-4 antibody-positive optic neuritis (AQP4-ON) presents a less favorable prognosis than other types of optic neuritis, there exists substantial heterogeneity in the prognostic outcomes within the AQP4-ON cohort. Considering the persistent debate over the role of MRI in assessing the prognosis of optic neuritis, we aim to investigate the correlation between the MRI appearance and long-term visual prognosis in AQP4-ON patients. Methods: We retrospectively reviewed the ophthalmological and imaging data of AQP4-ON patients admitted to our Neuro-ophthalmology Department from January 2015 to March 2018, with consecutive follow-up visits for a minimum of 3 years. Results: A total of 51 AQP4-ON patients (59 eyes) meeting the criteria were enrolled in this research. After assessing the initial orbital MR images of each patient at the first onset, we observed the involvement of the canalicular segment (p < 0.001), intracranial segment (p = 0.004), optic chiasm (p = 0.009), and the presence of LEON (p = 0.002) were significantly different between recovery group and impairment group. For quantitative measurement, the length of the lesions is significantly higher in the impairment group (20.1 ± 9.3 mm) than in the recovery group (12.5 ± 5.3 mm) (p = 0.001). Conclusion: AQP4-ON patients with involvement of canalicular, intracranial segment and optic chiasm of the optic nerve, and the longer range of lesions threaten worse vision prognoses. Timely MR examination during the initial acute phase can not only exclude the intracranial or orbital mass lesions but also indicate visual prognosis in the long term. [ABSTRACT FROM AUTHOR]

In 2020, a new disease was reported by Polovitskaya et al., caused by a monoallelic, gain-of-function mutation in CLCN6, encoding the ClC-6 Cl−/H±exchanger. Here, we report the ophthalmic findings of one of the first three patients with this disease (the proband) and review the findings in the other two patients in the literature. The CLCN6 gene is part of the voltage-dependent chloride channel protein family. It functions as either a chloride channel aiding in cell-volume regulation and acidification of intracellular organelles or as an antiporter, which are membrane proteins involved in the transport of molecules across a phospholipid membrane. This particular gene is found in late endosomes. Ion transport across endosome membranes is essential for endosomal function. The proband carried a de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6. The patient reported herein has a notable optic nerve appearance. The nerve initially appeared elevated. Over time, the optic nerve elevation appearance decreased, associated with progressive vision loss with a visual acuity of 20/470 at last follow-up. While Clcn6−/− mice have been found to have a mild neuronal lysosomal storage phenotype, the three reported children with a de novo c.1658A>G (p.Tyr553Cys) variant displayed significant developmental delay and neurodegeneration. [ABSTRACT FROM AUTHOR]

Glaucoma, a leading cause of irreversible blindness, poses a significant global health burden. Early detection is crucial for effective management and prevention of vision loss. This study presents a collection of novel structural biomarkers in glaucoma diagnosis. By employing advanced imaging techniques and data analysis algorithms, we now can recognize indicators of glaucomatous progression. Many research studies have revealed a correlation between the structural changes in the eye or brain, particularly in the optic nerve head and retinal nerve fiber layer, and the progression of glaucoma. These biomarkers demonstrate value in distinguishing glaucomatous eyes from healthy ones, even in the early stages of the disease. By facilitating timely detection and monitoring, they hold the potential to mitigate vision impairment and improve patient outcomes. This study marks an advancement in the field of glaucoma, offering a promising avenue for enhancing the diagnosis and possible management. [ABSTRACT FROM AUTHOR]

Background: Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. Methods: Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8–52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/− SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/− SEM 0.53 mmHg). Results: Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/− SEM 38.4 μm to 9.3 +/− SEM 22.1 μm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: −0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. Conclusions: SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) was used to measure in vivo local strains in the optic nerve (ON) associated with horizontal duction in humans. Axial and coronal MRI were collected in target-controlled gazes in 24 eyes of 12 normal adults (six males and six females, 59 ± 16 years) during large (~28°) and moderate (~24°) ductions. The ON, globe, and extraocular muscles were manually identified, and the pixels were converted to point-sets that were registered across different imaging planes and eye positions. Shape of the ON was parameterized based on point-sets. Displacements and strains were computed by comparing deformed with initial ON configurations. Displacements were the largest in the most anterior region. However, strains from adduction were uniform along the length of the ON, while those during abduction increased with distance from the globe and were maximal near the orbital apex. For large gaze angles, ON strain during abduction was primarily due to bending near the orbital apex that is less transmitted to the eye, but during adduction the ON undergoes uniform stretching that transmits much greater loading to the posterior eye, implied by greater strain on the ON.

A 4-year-old mixed-breed dog was presented for hyphema and glaucoma of the right eye. Enucleation of the right globe was carried out, and histopathology examination revealed an optic nerve glioma with incomplete surgical margins. At 8 wk after surgery, the dog had depressed mentation and a diminished pupillary light reflex of the left eye. Magnetic resonance imaging revealed an irregular, heterogeneously T2 hyperintense/T1 isointense mass in the region of the optic chiasm. Compression of the rostral thalamus was present, with effacement of the pituitary gland and involvement of the right orbit. The dog was euthanized 4.5 mo after initial presentation. An undefined glioma of the right optic nerve with extension to the diencephalon was diagnosed on necropsy. Key clinical message: Although rare, intraocular glioma is a differential diagnosis for hyphema, glaucoma, and retinal detachment. Magnetic resonance imaging should be considered in cases of intraocular neoplasia, notably in those with incomplete surgical margins of the optic nerve.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of

Glaucoma, a prevalent and potentially blinding eye disease, is linked to a variety of factors, including elevated intraocular pressure, optic nerve damage, and oxidative stress. In recent years, dietary habits, as a controllable lifestyle factor, have received increasing attention in the prevention and treatment of glaucoma. The purpose of this review was to investigate the effects of dietary factors on glaucoma, with a particular emphasis on two common dietary patterns: the high-salt diet and the Mediterranean diet. In addition, we investigated the association between many particular nutrients (including omega-3 fatty acids, vitamins, caffeine, and minerals) and glaucoma to fully assess the potential involvement of dietary variables in glaucoma pathogenesis, prevention, and treatment. This article reveals the importance of dietary components in glaucoma prevention and explores prospective possibilities for future research by conducting a comprehensive review of previous scientific studies.

Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in development for MT-ND4-LHON – is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.

Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.

Purtscher Retinopathy (PR) is also known as traumatic retinal angiopathy or lymphorrhagia retinae or retinal teletraumatism. It presents as occlusive retinal microvasculopathy distinguished by the presence of multiple retinal white lesions surrounding the optic nerve head and fovea, accompanied by perivascular clearing, often coinciding with intraretinal haemorrhages. Correlated conditions comprise of acute pancreatitis, crush injuries, severe head trauma, chest compression, long bone fractures, orthopaedic surgical procedures, Haemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) syndrome and battered baby syndrome. PR is a rare microvasculopathy, which is occlusive in nature and causes sudden and painless diminution of vision following serious trauma but might also be associated with non-traumatic aetiologies as well. The term Purtscher-like retinopathy is used when it occurs due to non-traumatic causes. Here, the authors present a case of a 25-year-old female, admitted to the hospital for severe abdominal pain, persistent nausea and multiple episodes of vomiting since two days. Her laboratory findings and radiological investigations revealed findings suggestive of acute pancreatitis. On day 2 of admission, she reported a bilateral diminution of vision. The ophthalmic evaluation revealed visual impairment and characteristic retinal findings of Purtscher flecken, cotton wool spots and few intraretinal haemorrhages mainly in the posterior pole. This case highlights the association between Purtscher-like retinopathy and acute pancreatitis. [ABSTRACT FROM AUTHOR]

Subacute Sclerosing Panencephalitis (SSPE) is a rare, slowly progressive disorder that affects the entire nervous system. It primarily involves the cerebral cortex, subcortex and optic nerves. Caused by a mutated strain of the measles virus, the disease is mostly irreversible and devastating. It presents with gradually progressive cognitive impairment, extrapyramidal symptoms and sometimes seizures. Although commonly seen in unvaccinated children, SSPE of adult onset is uncommon. The disease is fatal and currently has no treatment. There have been many different presentations of this disorder, ranging from optic nerve involvement to gradual cognitive decline, but none have a good prognosis; ultimately, patients may become akinetic and mute. Here, the authors present an uncommon case of SSPE occurring at an older age (26-year-old male), with a rapid and atypical presentation resembling severe post-viral syndrome, which was later diagnosed as SSPE. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) axons of the African clawed frog, Xenopus laevis, unlike those of mammals, are capable of regeneration and functional reinnervation of central brain targets following injury. Here, we describe a tadpole optic nerve crush (ONC) procedure and assessments of brain reinnervation based on live imaging of RGC-specific transgenes which, when paired with CRISPR/Cas9 injections at the one-cell stage, can be used to assess the function of regeneration-associated genes in vivo in F0 animals. Using this assay, we find that map3k12, also known as dual leucine zipper kinase (Dlk), is necessary for RGC axonal regeneration and acts in a dose-dependent manner. Loss of Dlk does not affect RGC innervation of the brain during development or visually driven behavior but does block both axonal regeneration and functional vision restoration after ONC. Dlk loss does not alter the acute changes in mitochondrial movement that occur within RGC axons hours after ONC but does completely block the phosphorylation and nuclear translocation of the transcription factor Jun within RGCs days after ONC; yet, Jun is dispensable for reinnervation. These results demonstrate that in a species fully capable of regenerating its RGC axons, Dlk is essential for the axonal injury signal to reach the nucleus but may affect regeneration through a different pathway than by which it signals in mammalian RGCs.

PURPOSE: Despite presumed relevance to ocular diseases, the viscoelastic properties of the posterior human eye have not been evaluated in detail. We performed creep testing to characterize the viscoelastic properties of ocular regions, including the sclera, optic nerve (ON) and ON sheath. METHODS: We tested 10 pairs of postmortem human eyes of average age 77 ± 17 years, consisting of 5 males and 5 females. Except for the ON that was tested in native shape, tissues were trimmed into rectangles. With physiologic temperature and constant wetting, tissues were rapidly loaded to tensile stress that was maintained by servo feedback as length was monitored for 1,500 sec. Relaxation modulus was computed using Prony series, and Deborah numbers estimated for times scales of physiological eye movements. RESULTS: Correlation between creep rate and applied stress level was negligible for all tissues, permitting description as linear viscoelastic materials characterized by lumped parameter compliance equations for limiting behaviors. The ON was the most compliant, and anterior sclera least compliant, with similar intermediate values for posterior sclera and ON sheath. Sensitivity analysis demonstrated that linear behavior eventually become dominant after long time. For the range of typical pursuit tracking, all tissues exhibit Debora numbers less than 75, and should be regarded as viscoelastic. With a 6.7 Deborah number, this is especially so for the ON during pursuit and convergence. CONCLUSIONS: Posterior ocular tissues exhibit creep consistent with linear viscoelasticity necessary for describing biomechanical behavior of the ON, its sheath, and sclera during physiological eye movements and eccentric ocular fixations. Running Head: Tensile Creep of Human Ocular Tissues.

Abstract Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the axon and transported back to the soma. This transport is essential since the final degradation of the vesicular content occurs only close to or in the soma. Here, we established an in vivo live-imaging model in the rat optic nerve using viral vector mediated LC3-labeling and two-photon-microscopy to analyze axonal transport of AVs. Under basal conditions in vivo, 50% of the AVs are moving with a majority of 85% being transported in the retrograde direction. Transport velocity is higher in the retrograde than in the anterograde direction. A crush lesion of the optic nerve results in a rapid breakdown of retrograde axonal transport while the anterograde transport stays intact over several hours. Close to the lesion site, the formation of AVs is upregulated within the first 6 h after crush, but the clearance of AVs and the levels of lysosomal markers in the adjacent axon are reduced. Expression of p150Glued, an adaptor protein of dynein, is significantly reduced after crush lesion. In vitro, fusion and colocalization of the lysosomal marker cathepsin D with AVs are reduced after axotomy. Taken together, we present here the first in vivo analysis of axonal AV transport in the mammalian CNS using live-imaging. We find that axotomy leads to severe defects of retrograde motility and a decreased clearance of AVs via the lysosomal system.

Abstract Background The pathophysiology of toxico-nutritional optic neuropathies remains debated, with no clear understanding of the respective roles played by the direct alcohol toxicity, smoking and the often associated vitamin deficiencies, which are risk factors for optic neuropathy. Our aim was to investigate genetic susceptibility in patients with bilateral infraclinical optic neuropathy associated with chronic alcohol use disorder. Methods This retrospective cohort study included 102 visually asymptomatic patients with documented alcohol use disorder from a French reference center. Optic neuropathy was identified with optical coherence tomography (OCT), after which genetic susceptibility in the group of affected patients was investigated. Genetic testing was performed using panel sequencing of 87 nuclear genes and complete mitochondrial DNA sequencing. Results Optic neuropathy was detected in 36% (37/102) of the included patients. Genetic testing of affected patients disclosed two patients (2/30, 6.7%) with optic neuropathy associated with pathogenic variants affecting the SPG7 gene and five patients (5/30, 16.7%) who harbored variants of uncertain significance close to probable pathogenicity in the genes WFS1, LOXL1, MMP19, NR2F1 and PMPCA. No pathogenic mitochondrial DNA variants were found in this group. Conclusions OCT can detect presence of asymptomatic optic neuropathy in patients with chronic alcohol use disorder. Furthermore, genetic susceptibility to optic neuropathy in this setting is found in almost a quarter of affected patients. Further studies may clarify the role of preventative measures in patients who might be predisposed to avoidable visual loss and blindness.

The development of the optic nerve and its surrounding tissues during the early fetal period is a convoluted period because it spans both the organogenesis period and the fetal period. This study details the microscopic anatomy and histoembryology of the optic nerve in embryos during the early fetal period, including the second half of the first trimester of pregnancy. Serial sections through the orbit of variously aged embryos allowed us to analyze the nerve in both longitudinal and transverse aspects. A histological assessment and description of the structures surrounding and inside the nerve were performed, highlighting the cellular subtypes involved. By employing immunohistochemical techniques, we could characterize the presence and distribution of astrocytes within the optic nerve. Our findings suggest that by the 8th gestational week (WG) the structures are homologs to all the adult ones but with an early appearance so that maturation processes take place afterward. By this age, the axons forming the nerve are definitive adult axons. The glial cells do not yet exhibit adult phenotype, but their aspect becomes adult toward the 13th week. During its development the optic nerve increases in size then, at 14 weeks, it shrinks considerably, possibly through its neural maturation process. The morphological primordium of the blood–nerve barrier can be first noted at 10 WG and at 13 WG the morphological blood–nerve barrier is definitive. The meningeal primordium can be first noted as a layer of agglomerated fibroblasts, later toward 13 WG splitting in pachymeninx and leptomeninges and leaving space for intrinsic blood vessels.

Glaucoma is a common and complex neurodegenerative disease characterized by progressive loss of retinal ganglion cells (RGCs) and axons. Currently, there is no effective method to address the cause of RGCs degeneration. However, studies on neuroprotective strategies for optic neuropathy have increased in recent years. Cell replacement and neuroprotection are major strategies for treating glaucoma and optic neuropathy. Regenerative medicine research into the repair of optic nerve damage using stem cells has received considerable attention. Stem cells possess the potential for multidirectional differentiation abilities and are capable of producing RGC-friendly microenvironments through paracrine effects. This article reviews a thorough researches of recent advances and approaches in stem cell repair of optic nerve injury, raising the controversies and unresolved issues surrounding the future of stem cells.

The review presents literature data about the anatomical structure, morphology and structural features of the optic nerve (ON). Four ON regions are detailed: intraocular, intraorbital, intracanalicular and intracranial. Specifically, the features of the intraocular region are outlined. It is divided into three zones: the surface nerve fiber layer, the prelaminar part and the lamina cribrosa of the sclera, which differ in histological structure and blood supply. The data on the coats of the intraorbital part include the details of the hard (dura mater), arachnoid and the soft (pia mater) coats. Other data represent the morphological structures of the intracanalicular and the intracranial parts of the ON. The distinctive features of blood supply in different ON regions are discussed.The information about the anatomical characteristics and structural features of the ON is important for studying the pathogenesis of the optic nerve´s damage.

Abstract Background To analyze the morphologic and functional change in traumatic optic neuropathy (TON) divided by the mechanism of optic nerve injury. Methods A retrospective analysis of 58 patients who were diagnosed as monocular TON from February 2015 to August 2021 was conducted at in CHA Bundang Medical Center in Seongnam, South Korea. The patients visited the clinic of the department of ophthalmology for more than 6 months and at least 4 times during this period. Results 44 patients were classified as blunt TON patients, and 14 patients were surgical TON patients. The visual acuity showed significant decrease in traumatic eyes at the first visit after injury compared to fellow eyes and maintained the injured status during the 1-year follow-up period in blunt TON. In surgical TON, the visual acuity slightly improved during 1 month follow-up period. RNFL thickness tended to be decreased at 1 month after first visit blunt TON patients, which was earlier than surgical TON patients. GCIPL thickness showed earlier decreased than RNFL thickness in both blunt and surgical TON patients. Conclusions In both blunt and surgical TON eyes, there was a notable thinning in both RNFL and GCIPL, with particularly remarkable reduction in GCIPL in early phase. Therefore, analyzing each retinal layer thickness using OCT in conjunction with assessing visual function would be necessary. This combined approach is not only crucial for understanding clinical courses of each TON, but also predicting the morphological and functional deteriorations in TON.

Abstract Leber’s hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.

Dysthyroid optic neuropathy is an important secondary pathological condition of thyroid-associated ophthalmopathy, characterized clinically by several clinical manifestations, including reduced visual acuity, impairment of color vision, relative afferent pupillary defect, and optic disk edema or atrophy. Ophthalmological auxiliary examination shows abnormal vision field and visual evoked potential, etc., and imagining examination shows orbital apex crowding, which can assist diagnosis. The pathogenesis of this disease is still unclear. With previous studies proposing that it was related to optic nerve compression, stretch, and ischemia. Treatment methods include high-dose intravenous glucocorticoid, orbital decompression, orbital radiation therapy, and biological agent. This article systematically reviews the research progress on the epidemiological characteristics, pathogenesis, diagnosis, and treatment of this disease, with a view to providing useful reference for future in-depth clinical practice and scientific research.

ABSTRACTGlaucoma encompasses a spectrum of disorders characterized by the chronic degeneration of retinal ganglion cell (RGC) axons and the progressive loss of RGCs, resulting in visual impairment. In this study, we investigated the effect of autophagy deficiency on two glaucoma hypertensive models, the DBA/2J spontaneous glaucoma model, and the TGFβ2 (transforming growth factor β2) chronic ocular hypertensive model. For this, we used the Atg4b−/− and DBA/2J-Atg4b−/− mice, this latter generated in our laboratory via CRISPR/Cas9 technology, which display impaired autophagy. In contrast to littermate WT controls, mice deficient in Atg4B, did not develop glaucomatous elevation of intraocular pressure (IOP). Moreover, autophagy deficiency protected against RGC death and optic nerve atrophy. Collectively, our data supports a pathogenic role of autophagy in the context of ocular hypertension and glaucoma.Abbreviations: ATG4B: Autophagy-related 4B; BAX: BCL2-associated X protein; BECN1: Beclin 1; BID: BH3 interacting domain death agonist; CASP8: Caspase 8; IOP: Intraocular Pressure; MAP1LC3B: microtubule-associated proteins 1B; ON: Optic Nerve; RGC: Retinal Ganglion Cells; SQSTSM1: Sequestosome 1; TBK1: TANK-binding kinase 1; TGFβ2: Transforming Growth Factor β2; WT: Wild Type.

BACKGROUND/AIMS: Neonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants. METHODS: We prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models. RESULTS: 83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI -15.9 to -4.9) lower in infants with than without sepsis/NEC in the univariable analysis (p

This study describes the development of a convolutional neural network (CNN) for automated assessment of optic disc photograph quality. Using a code-free deep learning platform, a total of 2377 optic disc photographs were used to develop a deep CNN capable of determining optic disc photograph quality. Of these, 1002 were good-quality images, 609 were acceptable-quality, and 766 were poor-quality images. The dataset was split 80/10/10 into training, validation, and test sets and balanced for quality. A ternary classification model (good, acceptable, and poor quality) and a binary model (usable, unusable) were developed. In the ternary classification system, the model had an overall accuracy of 91% and an AUC of 0.98. The model had higher predictive accuracy for images of good (93%) and poor quality (96%) than for images of acceptable quality (91%). The binary model performed with an overall accuracy of 98% and an AUC of 0.99. When validated on 292 images not included in the original training/validation/test dataset, the model's accuracy was 85% on the three-class classification task and 97% on the binary classification task. The proposed system for automated image-quality assessment for optic disc photographs achieves high accuracy in both ternary and binary classification systems, and highlights the success achievable with a code-free platform. There is wide clinical and research potential for such a model, with potential applications ranging from integration into fundus camera software to provide immediate feedback to ophthalmic photographers, to prescreening large databases before their use in research.

The Xenopus retinotectal circuit is organized topographically, where the dorsal-ventral axis of the retina maps respectively on to the ventral-dorsal axis of the tectum; axons from the nasal-temporal axis of the retina project respectively to the caudal-rostral axis of the tectum. Studies throughout the last two decades have shown that mechanisms involving molecular recognition of proper termination domains are at work guiding topographic organization. Such studies have shown that graded distribution of molecular cues is important for topographic mapping. However, the complement of molecular cues organizing topography along the developing optic nerve, and as retinal axons cross the chiasm and navigate towards and innervate their target in the tectum, remains unknown. Down syndrome cell adhesion molecule (DSCAM) has been characterized as a key molecule in axon guidance, making it a strong candidate involved in the topographic organization of retinal fibers along the optic path and at their target. Using a combination of whole-brain clearing and immunohistochemistry staining techniques we characterized DSCAM expression and the projection of ventral and dorsal retinal fibers starting from the eye, following to the optic nerve and chiasm, and into the terminal target in the optic tectum in Xenopus laevis tadpoles. We then assessed the effects of DSCAM on the establishment of retinotopic maps through spatially and temporally targeted DSCAM knockdown on retinal ganglion cells (RGCs) with axons innervating the optic tectum. Highest expression of DSCAM was localized to the ventral posterior region of the optic nerve and chiasm; this expression pattern coincides with ventral fibers derived from ventral RGCs. Targeted downregulation of DSCAM expression on ventral RGCs affected the segregation of medial axon fibers from their dorsal counterparts within the tectal neuropil, indicating that DSCAM plays a role in retinotopic organization. These findings together with previous studies demonstrating cell-autonomous roles for DSCAM during the development of pre- and postsynaptic arbors in the Xenopus retinotectal circuit indicates that DSCAM exerts multiple roles in coordinating axon targeting and structural connectivity in the developing vertebrate visual system.

Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the axon and transported back to the soma. This transport is essential since the final degradation of the vesicular content occurs only close to or in the soma. Here, we established an in vivo live-imaging model in the rat optic nerve using viral vector mediated LC3-labeling and two-photon-microscopy to analyze axonal transport of AVs. Under basal conditions in vivo, 50% of the AVs are moving with a majority of 85% being transported in the retrograde direction. Transport velocity is higher in the retrograde than in the anterograde direction. A crush lesion of the optic nerve results in a rapid breakdown of retrograde axonal transport while the anterograde transport stays intact over several hours. Close to the lesion site, the formation of AVs is upregulated within the first 6 h after crush, but the clearance of AVs and the levels of lysosomal markers in the adjacent axon are reduced. Expression of p150Glued, an adaptor protein of dynein, is significantly reduced after crush lesion. In vitro, fusion and colocalization of the lysosomal marker cathepsin D with AVs are reduced after axotomy. Taken together, we present here the first in vivo analysis of axonal AV transport in the mammalian CNS using live-imaging. We find that axotomy leads to severe defects of retrograde motility and a decreased clearance of AVs via the lysosomal system. [ABSTRACT FROM AUTHOR]

Background: We describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL) with central nervous system (CNS) involvement. Case presentation: A 65-year-old Asian female with Ph+-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph+-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased. Conclusions: To the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse. [ABSTRACT FROM AUTHOR]